Piperazine derivatives: synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase and SAR studies

Eur J Med Chem. 2015 Jan 27;90:436-47. doi: 10.1016/j.ejmech.2014.11.034. Epub 2014 Nov 18.

Abstract

The Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) catalyzes hydride transfer to long-chain enoyl thioester substrates. MtInhA is a member of the mycobacterial type II dissociated fatty acid biosynthesis system, and is the bona fide target for isoniazid, the most prescribed drug for tuberculosis treatment. Here, a series of piperazine derivatives was synthesized and screened as MtInhA inhibitors, which resulted in the identification of compounds with IC50 values in the submicromolar range. A structure-activity relationship (SAR) evaluation indicated the importance of the chemical environment surrounding the carbonyl group for inhibition. In addition, the structure of one selected compound was supported by crystallographic studies, and experimental geometrical values were compared with semi-empirical quantum chemical calculations. Furthermore, the mode of inhibition and inhibitory dissociation constants were determined for the nine most active compounds. These findings suggest that these 9H-fluoren-9-yl-piperazine-containing compounds interact with MtInhA at the enoyl thioester (2-trans-dodecenoyl-CoA) substrate binding site.

Keywords: Enoyl-ACP reductase; InhA inhibition; Mycobacterium tuberculosis; Piperazines; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / metabolism
  • Enzyme Activation / drug effects
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / enzymology*
  • Piperazine
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Piperazines
  • Piperazine
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)